1. Field of the Invention
This invention relates to novel pharmaceutical compositions of matter comprising N-alkyl-4'-hydroxyacetanilide, which have analgesic, antipyretic, antiinflammatory and sedative activity, but lack the nephrotoxicity and hepatotoxicity of acetaminophen. This invention further relates to a method of ameliorating pain through the administration of these compounds.
2. Description of the Related Art
Acetaminophen (paracetamol) has become increasingly popular as an analgesic, despite the fact that its heptatoxicity has been documented since 1966. D. G. Davidson and W. N. Eastham, British Medical Journal 2:497-499 (1966). It has recently been shown that chronic ingestion of therpeutically recommended doses of acetaminophen in humans for extended periods of time can cause massive hepatic necrosis. A. J. Ware, et al., Annals of Internal Medicine 88:267-268 (1978); D. M. Rosenberg and F. A. Neelon, Annals of Internal Medicine 88:129 (1978); J. D. Barker, Jr., Annals of Internal Medicine 87:299-301 (1977) and G. K. Johnson and K. G. Tolman, Annals of Internal Medicine 87:302-303 (1977). Individuals with underlying liver injury or disease have been found to be particularly susceptible to acetaminophen-mediated hepatotoxicity. D. M. Rosenberg, et al., Southern Medical Journal 70:600-601 (1977); H. L. Bonkowsky, et al., Lancet 2:1016-1018 (1978); V. Schoenfeld, et al., New England Journal of Medicine 303:47 (1980 ); and D. P. Golden et al., Oral Surgery 51:385-389 (1981). Additionally, conditions which induce the liver enzymes responsible for the metabolization of acetaminophen, such as consumption of alcohol or barbituates, will markedly potentiate the heptatoxicity of this compound.
Studies by Nebert with inbred mice have suggested that acetaminophen can cause cataracts in humans. Science, 200:539-541 (1978). Acetaminophen has also recently been implicated as a possible human carcinogen. M. I. Mihatasch, et al., Schweizerische Medizonische Wochenschrift 110:255-264 (1980). Thus, acetaminophen, which is an ubiquitious component of over-the-counter and prescription drugs, may present a serious risk to general users and sensitive user subpopulations in terms of its hepatic and other toxic effects.
The mechanism of acetaminophen toxicity is not fully understood in the prior art. Editorial, Lancet 2:1189 (1975); B. E. Walker, et al., Clinical Science & Molecular Medicine 47:449-459 (1974). However, recent studies, which are discussed infra, suggest the involvement of certain hepatic enzyme systems which convert acetaminophen into a toxic metabolite or produce a toxic by-product.
Because such diverse compounds as cysteamine, methionine, cysteine, dimethlymercaptol, selenium and vitamin E have afforded varying degrees of protection in man and experimental animals against the hepatotoxicity of acetaminophen, and because these compounds under certain circumstances can act as antioxidants, it has been suggested that other antioxidants would also provide protection. J. Kelleher, et al., Journal of Internal Medical Research 4, Supplement (4):138-144 (1976). Compounds such as 2-methylthiazolidine-4-carboxylic acid which form cysteine in the liver can also protect against heptotoxins. Chemical & Engineering News, Aug. 2, 1982 at p. 18.
Animal studies indicate that antioxidants can provide limited protection against the hepatotoxic effects of acetaminophen. For example, .alpha.-tocopherol protects vitamin E deficient rats. B. E. Walker, et al., supra; J. Kelleher, et al., supra. It has been reported that vitamin C may also provide such protection. T. C. Raghuram, et al., Toxicology Letters 2:175-178 (1978).
U.K. patent application No. 2,040,164 and U.S. Pat. No. 4,292,298 (assigned to Beecham Group Ltd.), both claim compositions and methods for reducing the acute liver toxicity effects of acetaminophen by the oral administration of a co-formulation with ascorbic acid. The U.S. patent discloses that 300 mg/kg of ascorbic acid in nonsustained release form had no protective effect against 450 mg/kg (orally) of paracetamol whereas the same amount of ascorbic acid in sustained release form had substantial protective effect and 600 mg/kg and even greater effect.
However, in an experimental study in man, although vitamin C caused a rapid and pronounced decrease in the excretion rate of acetaminophen sulfate, it did not affect the apparent half-life of the drug, as evidenced by its rate of secretion as such in the urine, or as glycuronide or its sulfate. J. B. Houston and G. Levy, Journal of Pharmacetical Science 65:1218-1221 (1976). It was stated that the specific interaction between acetaminophen and ascorbic acid was probably of little clinical significance under usual conditions; that is, when acetaminophen is taken in single recommended doses as an analgesic or antipyretic. Other researchers concluded that the protective effects manifested by these vitamins cannnot be attributed to their anti-oxidant activity, because whereas vitamin E and propyl gallate reduce heptatotoxicity, diphenyl-p-phenylene-diamine (DDPD), an antioxidant in vitro and one which give protection against CCl.sub.4 hepatotoxicity, enhances acetaminophen hepatotoxicity. J. Kelleher et al., supra. These authors speculated that the modification of hepatotoxicity may result from an alteration in the activity of specific components of the microsomal drug-metabolizing enzyme systems.
Suprisingly and notwithstanding the published literature reporting that some antioxidants may provide protection against the heptatotoxic effects of acetaminophen, I have found that the omnipresent antioxidants BHT (butylated hydroxytoluene) and BHA (butylated hydroxyanisole), which have been used in foods to prevent spoilage, profoundly enhance its hepatotoxicity. Because the general population ingests large amounts of these chemicals daily due to their presence in a wide variety of food products, the likelihood of an increased incidence of hepatotoxicity in persons taking repeated dosages of acetaminophen is self-evident.
Other approaches to ameliorating acetaminophen-mediated hepatotoxicity have also been considered. For example, a news release quoted a publication in "The Medical Letter" which reported a clinical study showing that N-acetylcysteine is effective in preventing hepatotoxicity if administered with in 16 hours after an overdose. Washington Post, Dec. 7, 1979, page A9. The authors chose N-acetylcysteine because of its chemical similarity to glutathione, the substantce which the body employs to detoxify the drug.
Dimethyl sulfoxide (DMSO) has been shown to protect mice against the hepatotoxic effects of acetaminophen when administered up to one hour after administration of acute toxic amounts of acetaminophen. C. P. Seigers, Journal of Pharmacology 30:375-377 (1978). Its activity was attributed to inhibition of microsomal oxidation of the drug by the the hepatic mixed-function oxidase system due to chemically reactive alkylating agents. On the other hand, this theory would fall to explain the inability of DMSO to protect mice against CCl.sub.4 hepatotoxicity, since this compound is also activated by the mixed function oxidase system. The authors therefore were unable to provide the acetaminophen-antihepatotoxic mechanism of DMSO.
It is apparent from the foregoing that an effective method of protecting humans against acute acetaminophen hepatotoxicity had not been established by the prior art. Furthermore, it may be preferable to restrict the use of acetaminophen per se, rather than merely administering it concurrently with an ameliorating agent. Like so many other toxic chemicals, once the mechanism by which acetaminophen initiates hepatotoxicity is understood, the potential risk to human health from acute and chronic exposure to this drug can be better assessed and avoided.
The risk of severe hepatic damage is high in patients who take acetaminophen in combination with drugs that are known to induce cytochrome P-450 (the enzyme responsible for the bioactivation of acetaminophen to its toxic intermediate). N. Buchanan and G. P. Moodley, British Medical Journal 2:307-308 (1979); N. Wright and L. F. Arthurs and J. F. Fielding, Journal of the Irish Medical Association 73:273-274 (1980). Alcohol has been demonstrated to induce cytochrome P-450, P. S. Misra, et al., American Journal of Medicine 51:346-351 (1971), so it is not surprising that acetaminophen-mediated hepatotoxicity is markedly increased by chronic use of ethanol. D. J. Emby and B. N. Fraser, South African Medical Journal 51:208-209 (1977); R. Goldfinger, et al., American Journal of Gastrology 70:385-388 (1978); C. J. McClain, et al., Journal of the American Medical Association 224:251-253 (1980); and H. Light, et al., Annals of the Internal Medicine 92:511 (1980).
At the present time, there are over 300 drugs in use that have been shown to induce cytochrome P-450, and in doing so should promote the hepatotoxicity of acetaminophen. For example, the well-known cytochrome P-450 inducer, phenobarbital, is an effective and widely prescribed drug for certain types of epilepsy. Therefore, the chronic use of acetaminophenin individuals with grand mal should be contraindicated. Although tobacco is also known to induce cytochrome P-450, W. J. Jusko, Drug Metabolism Reviews 9:221-236 (1979), at present, there is no information indicating whether or not smoking promotes the toxicity of acetaminophen.
In 1973, Mitchell and co-workers published a series of papers which demonstrated that cytochrome P-450 participates in the activation of acetaminophen to its toxic intermediate. J. R. Mitchell, et al., Journal of Pharmacology and Experimental Therapeutics 187:185-194 (1973); D. J. Jollow, et al., Journal of Pharmacology and Experimental Therapeutics 187:195-202 (1973); and W. Z. Potter, et al., Journal of Pharmacology and Experimental Therapeutics 187:203-217 (1973). Nevertheless, the nature of this metabolite and the mechanism by which acetaminophen initiates hepatotoxicity were not established.
It was originally proposed that cytochrome P-450 oxidizes acetaminophen to N-hydroxyacetaminophen, which then loses water to give the hypothesized intermediate N-acetyl-p-benzoquinone imine. If this intermediate is produced, it could be detoxified by reaction with reduced glutathione (GSH) to yield 3-(glutathion-S-yl)-acetaminophen. J. A. Hinson, et al., Drug Metabolism Disposition 10:47-50 (1982); however, when GSH is depleted, this quinone imine binds to cellular macromolecules. W. Z. Potter, et al., Pharmacology 12:129-143 (1974). Based on these findings, it has been proposed that covalent binding of N-acetyl-p-benzoquinone imine to intracellular macromolecules is responsible for the cell death that is manifested as hepatic injury. Potter, et al., supra. Recent studies by J. A. Hinson, et al., Life Science 24:2133-2138 (1979) and S. D. Nelson, et al., Biochemical Pharmacology 29:1617-1620 (1980) cast doubt on aspects of this mechanism. These investigators have demonstrated that if N-acetyl-p-benzoquinone imine is the toxic species, it is biosynthesized by a pathway that does not include N-hyroxyacetaminophen.
An alternative hypothesis to account for the formation of N-acetyl-p-benzoquinone imine envisions the epoxidation of acetaminophen followed by ring opening with loss of water. If such a mechanism were correct, then the addition of heavy oxygen (O.sup.18 2) to the reaction mixture would lead to the incorporation of O.sup.18 into half of the N-acetyl-p-benzoquinone imine. However, when such a study was conducted, the investigators were unable to detect O.sup.18 in any of the acetaminophen metabolites, S. D. Nelson, et al., supra; and J. A. Hinson, et al., Drug Metabolism Disposition 8:289-294 (1980).
A third mechanism suggests that cytochrome P-450 initiates a one-electron oxidation of acetaminophen, giving acetaminophen free radical. S. D. Nelson, et al., Molecular Pharmacology 20:195-199 (1981). Transfer of an electron from this free radical to oxygen would produce a superoxide free radical and N-acetyl-p-benzoquinone imine. Support for such an hypothesis and for the participation of this reaction pathway in hepatotoxicity comes from the observation that acetaminophen can be oxidized to a free radical which exhibits all of the electrophilic properties assigned to the hypothetical toxic intermediate. S. D. Nelson, et al., Molecular Pharmacology 20:195-199 (1981). The possibility of a free radical mechanism of hepatotoxicity is further supported by the demonstration that promethazine, A. E. M. McLean and L. Nuttall, Bio-chemical Pharmacology 27:425-430 (1978); glutathione, M. Strolin-Beneditte, et al., Journal of Pharmaceutics and Pharmacology 27:629-632 (1975), and A. R. Burkitt, et al., Biochemical Pharmacology 28:2941-2946 (1979); and .beta.-dimethylaminoethanol, C. P. Siegers and M. Young, Arzneimittel Forschung 29:520-523 (1979), which are known free radical scavengers, afford protection against acetaminophen toxicity.
I have found that acetaminophen-mediated chronic and acute hepatotoxicity is due to the formation of superoxide free radicals, according to what I believe to be the following mechanism: ##STR1##
Acetaminophen is metabolized by first being converted to the acetaminophen free radical by cytochrome P-450. This toxic free radical is oxidized to N-acetyl-p-benzoquinone imine, which is normally eliminated by conversion by glutathione in the liver to the glutathione-acetaminophen thiether. The oxidation of the acetaminophen free radical to N-acetyl-p-benzoquinone imine produces the toxic superoxide free radical which is dismuted to H.sub.2 O.sub.2, which is eliminated by peroxidase enzymes. However, when there are insufficient glutathione levels in the liver to react with the N-acetyl-p-benzoquinone imine produced by this mechanism, it can be reconverted by reductase to the acetaminophen free radical while thus generating additional toxic superoxide free radical. This cyclic regeneration of the acetaminophen free radical generates sufficient superoxide free radical to overwhelm the naturally occurring superoxide dismutase (SOD), thereby promoting hepatotoxicity through lipid peroxidation.
In my U.S. Pat. No. 4,314,989, I disclosed methods and compositions for preventing acetaminophen-induced hepatotoxicity by employing methionine sulfoxide to destroy the toxic acetaminophen free radical before it has the opportunity to react with oxygen.
The present invention is based on my finding that certain N-alkyl-4'-hydroxyacetanilide compounds possess analgesic activities comparable to acetaminophen but lack its nephrotoxicity and hepatotoxicity. These compounds are not metabolized by the liver enzyme reactions in a manner which produces the toxic intermediate superoxide free radical.
Certain members of this genus are disclosed as starting materials for other compounds having uses unrelated to analgesia in British Pat. No. 749,907 (1956), and at Chemical Abstracts 51:1265i. In 1894, O. Hinsberg and G. Treuple, Archives of Experimental Pathology and Pharmacology 33:216-250 (1894), synthesized a number of p-amidophenols and examined their antipyretic and analgesic activities. Among the tested compounds was N-ethyl-4'-hydroxyacetanilide. In this paper, the authors presented data on its antipyretic activity, however, they concluded that this compound had no antipyretic activity. They also stated, without supporting data, that N-ethyl-4'-hydroxyacetanilide had no analgesic properties. This is contrary to my findings using an accepted hot plate analgesic model. In that same year, German Pat. No. 79,098 was granted to A. M. Hochst for the synthesis of N-ethyl-4'-hydroxyacetanilide. The patent states that the products are useful as medicaments, without identifying the conditions for which it might have utility or any methods of use. In 1899, Hinsberg, Liebig's Annual 305:276-289 (1899) published a more detailed synthesis of N-ethyl-4'-hydroxyacetanilide than is found in his 1894 paper. No biological activity is discussed in this article.
It is the object of this invention to provide novel pharmaceutical compositions which have acetaminophen's analgesic activity, but are nonhepatotoxic; and further, to provide methods for their use. A further object is to provide novel N-alkyl-4'-hydroxyacetanilides.